The use of deep hypothermia (<20C) for cerebral protection ushered in the modern era of safe and effective operations on the heart and aorta. In large part due to advanced circulatory management strategies, surgical procedures on the proximal aorta and arch utilizing deep hypothermic circulatory arrest have steadily increased over the last decade. Despite these advances, neurologic complications remain a sobering limitation. Indeed, 7%-13% of patients endure permanent neurologic dysfunction. In addition, postoperative cognitive decline (POCD) occurs in 36% of cardiac surgery patients at 6 weeks after surgery, and importantly, persists in 42% of patients up to 5 years after surgery and reduces quality of life. Although deep hypothermia has been the standard of care for decades in adult patients requiring circulatory arrest, moderate hypothermia is now more commonly used in many centers. However, this transition to moderate temperatures has been based entirely on observational studies that have not adequately assessed neurological or neurocognitive outcomes. Little is more devastating to a patient or the patient's family than to have a successful operation that prolongs life, but is complicated by cognitive impairment resulting in a diminished quality of life and loss of functional in- dependence. The long-term goal of our multidisciplinary Neurologic Outcome Research Group is to understand the mechanisms underlying neurologic and neurocognitive dysfunction after cardiac surgery, and to reduce the incidence of these devastating outcomes. In the proposed study, we will test our hypothesis that deep hypo- thermia (<20C) during surgical circulatory arrest limits POCD and preserves brain connectivity to a greater degree than moderate hypothermia (24.1C-28C) and that low hypothermia (20.1C-24C) is non-inferior to deep hypothermia. Thus the primary aims of our prospective, randomized clinical trial are to 1) determine the effect of deep vs low vs moderate hypothermia on neurocognitive function and quality of life after surgical cir- culatory arrest; 2) determine the effect of deep vs low vs moderate hypothermia on brain connectivity and met- abolic signatures of neuronal damage following surgical circulatory arrest; and 3) determine how temperature management affects leukocyte SUMOylation patterns as a mechanism of inflammatory modulation in surgeries employing circulatory arrest. Our proposed study will be the first randomized trial to evaluate the effects of deep vs low vs moderate hypothermia during circulatory arrest on neurocognitive function and functional brain connectivity. Our preliminary data strongly supports a detrimental effect of moderate hypothermia during circu- latory arrest and thus this study is likely to dramatically alter practice and improve patient safety. This study will also be the first study in humans to assess the role of the small ubiquitin-like modifier conjugation pathway in protecting the brain during cardiac surgery requiring circulatory arrest. Thus, this study is significant, and will vertically advance the field of cardiac surgery by revolutionizing our understanding of the effects of hypother- mia on neurologic and neurocognitive outcomes, by providing strong evidence for optimal hypothermic tem- peratures during surgical circulatory arrest, and by identifying new targets for therapeutic intervention to in- crease the resistance of organs to a transient interruption in blood supply.